Alzheimer's Disease (AD) is a major international health problem with unknown etiology and pathogenesis. This program project grant unites a multidisciplinary group of clinical and basic scientists to address a number of etiologic or pathogenetic mechanisms in AD. A Core facility provides extraneural tissue from living AD patients or autopsied brain tissue from thoroughly evaluated and longitudinally followed AD patients. Project 1 will assay neuronotrophic factor alterations in AD and correlate these changes with classic AD morphological markers (NFT and SP). Cholinergic markers (CAT/AChE), using laminar microchemical techniques, will be directly correlated with morphological markers. Project 2 will study levels, precursors, metabolites and receptor binding of the monoaminergic system in the nucleus basalis of Meynert, hippocampus and cerebral cortex and correlate these with cholinergic markers and classic morphologic markers in AD. Project 3 will study brain trace element levels to define potential neurotoxic elements and/or imbalances in AD and control brains, utilizing instrumental and radiochemical neutron activation analyses, correlated with scanning electron microscopy microprobe analyses. Hair and fingernail trace element levels will be determined in AD patients followed longitudinally and in twins, one of whom has AD. Project 4 will define alterations in AD erythrocyte membrane cytoskeletal proteins utilizing electron spin resonance labeling. Choline efflux and transport properties of AD erythrocyte membranes will be studied to define an extraneural marker for AD. Project 5 will investigate protein synthesis in AD brains utilizing a cell free system and in situ labeling. The relationship of cap-binding protein to neurofilaments and NFT will be studied using immunocytochemical and immunoblotting techniques and the structure and properties of messenger RNA in AD and control will be compared. This program project grant, with the opportunity for correlative clinical, morphological and biochemical studies of longitudinally follow AD patients, offers the tremendous potential to further understanding of this disease.